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Critical role of both p27 KIP1 and p21 CIP1/WAF1 in the antiproliferative effect of ZD1839 (‘Iressa’), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells
Author(s) -
Di Gennaro Elena,
Barbarino Marcella,
Bruzzese Francesca,
De Lorenzo Sonya,
Caraglia Michele,
Abbruzzese Alberto,
Avallone Antonio,
Comella Pasquale,
Caponigro Francesco,
Pepe Stefano,
Budillon Alfredo
Publication year - 2003
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10239
Subject(s) - cyclin dependent kinase , cancer research , epidermal growth factor receptor , cyclin dependent kinase 2 , biology , cell cycle , cell growth , epidermal growth factor , cell cycle checkpoint , cyclin d1 , tyrosine kinase , g1 phase , kinase , microbiology and biotechnology , signal transduction , cell , protein kinase a , receptor , biochemistry
High expression of the epidermal growth factor receptor (EGFR) has been implicated in the development of squamous‐cell carcinomas of head and neck (SCCHN). ZD1839 (‘Iressa’) is an orally active, selective EGFR‐TKI (EGFR‐tyrosine kinase inhibitor) that blocks signal transduction pathways implicated in proliferation and survival of cancer cells, and other host‐dependent processes promoting cancer growth. We have demonstrated that ZD1839 induces growth arrest in SCCHN cell lines by inhibiting EGFR‐mediated signaling. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a G1 arrest together with a partial G2/M block; this was associated with increased expression of both p27 KIP1 and p21 CIP1/WAF1 cyclin‐dependent kinase (CDK) inhibitors. The activity of CDK2, the main target of CIP/KIP CDK inhibitors, was reduced in a dose‐dependent fashion after 24 h of ZD1839 treatment and this effect correlated to the increased amount of p27 KIP1 and p21 CIP1/WAF1 proteins associated with CDK2‐cyclin‐E and CDK2‐cyclin‐A complexes. In addition, ZD1839‐induced growth inhibition was significantly reduced in cell transfectants expressing p27 KIP1 or p21 CIP1/WAF1 antisense constructs. Overall, these results as well as the timing of the effect of ZD1839 on G1 arrest and p27 KIP1 and p21 CIP1/WAF1 upregulation, suggest a mechanistic connection between these events. © 2003 Wiley‐Liss, Inc.